Albendazole Sulfone Research Articles

Simultaneous determination of albendazole sulfoxide enantiomers and albendazole sulfone in plasma

A high-performance liquid chromatographic method has been developed for the simultaneous determination of albendazole sulfoxide (ABZSO) enantiomers and albendazole sulfone (ABZSO 2) in human plasma. The resolution of ABZSO enantiomers and ABZSO 2 was obtained on a Chiralpak ® AD column using hexane–isopropanol–ethanol (81:14.25:4.75, v/v/v) as the mobile phase. The drugs were detected by fluorescence ( λ exc=280 nm, λ em=320 nm). The drugs were extracted from 500 μl plasma with ethyl acetate, and after solvent evaporation, the residues were dissolved in the mobile phase and chromatographed. The method was precise and accurate for the three compounds, as judged by the coefficients of variation and relative errors observed. Linear standard curves were obtained in the concentration range of 5–2500 ng/ml for ABZSO enantiomers and 1–500 ng/ml for ABZSO 2. A typical plasma concentration–time profile is presented for one patient under treatment for neurocysticercosis.

Disposition of Netobimin, Albendazole, and Its Metabolites in the Pregnant Rat: Developmental Toxicity

Netobimin (NTB), a benzimidazole prodrug with a good anthelmintic spectrum, was administered orally to female rats at a dose of 59.5 mg NTB/kg, to study its pharmacokinetic behavior and the disposition of its most important metabolites, albendazole (ABZ), albendazole sulfoxide (ABZSO), and albendazole sulfone (ABZSO2). ABZ was found in plasma after 6 hr. Peak plasma concentrations (Cmax) and areas under curves (AUC) of ABZSO were eight- and fourfold higher, respectively, than those of ABZSO2. To study NTB disposition in pregnant rats, three different drug doses (50, 59.5, and 70.7 mg/kg) were given. No significant differences were found between plasma concentrations for each metabolite at the three doses studied. Only ABZ concentrations rose slightly as dose increased. ABZ, ABZSO, and ABZSO2were found in amniotic sacs and embryos at concentrations that were higher than plasma at the same times. The fetuses obtained after administration of each of the doses of NTB were studied to detect developmental toxicity. A significant correlation was found between rate of developmental toxicity and metabolite concentration. ABZSO embryo concentrations could be the main factor accounting for toxicity.

Rapid Quantitative Screening Assay of Trace Benzimidazole Residues in Milk by Liquid Chromatography

A simple, rapid, and sensitive liquid chromatographic (LC) assay for quantitative screening of albendazole 2-aminosulfone, albendazole sulfoxide, oxibendazole, oxfendazole, albendazole sulfone, p-hydroxyfenbendazole, albendazole, mebendazole, fenbendazole sulfone, and fenbendazole residues in milk was developed. Samples are made basic (pH 10) and extracted with ethyl acetate. Extracts are partitioned with water, evaporated to dryness, reconstituted with mobile phase, and analyzed isocratically by ion-pair reversed-phase LC at 292 nm. Overall recoveries ranged from 79 to 100%. Linearity was excellent in the fortification range examined (5.3-200 ng/mL). Precision data, based on within- and between-days variations, suggested an overall relative standard deviation of 2.0 to 5.8%. The method was successfully used to quantitate albendazole and fenbendazole and metabolites in milk from 2 drug-treated dairy cows.

The pharmacokinetics of albendazole metabolites following administration of albendazole, albendazole sulfoxide and netobimin to one-month- and eight-month-old sheep

The principal metabolites detected in plasma of sheep following oral administration of albendazole (ABZ), albendazole sulfoxide (ABSO) and netobimin (NTB) each at 5.0 mg kg −1 body weight were ABSO and albendazole sulfone (ABSO 2). The areas under the plasma concentration-time curve (AUC) for ABSO and ABSO 2 were significantly (P<0.05) larger following administration for ABSO than NTB in 1-month- and 8-month-old sheep. The AUC for the ABSO and ABSO 2 metabolites were larger following administration of ABZ than NTB in 1-month- but not 8-month-old sheep and the AUC of the ABSO and ABSO 2 metabolites were greater following ABSO than ABZ as parent compound in 8-month-old sheep only. The larger AUC values for metabolites following administration of ABSO as the parent compound were generally coincident with significantly higher maximum (C max) concentrations and not with persistence in the body, since mean residence times (MRT) of the metabolites were not significantly different from those determined following ABZ and NTB as parent compounds. The lower metabolite concentration following administration of NTB may have been a feature of its requirement for metabolic conversion and its larger molecular weight. Correction of AUC values for molecular weight removed any significant differences between AUC values for either metabolite in 8-month-old lambs. The corrected metabolite AUCs following NTB were, however, significantly lower than those following ABSO adminstration in 1-month-old lambs, suggesting that immature metabolic processes in these animals contributed to the lower relative bioavailability of NTB in this age group. Age did not affect the disposition of metabolites following ABZ or ABSO but the AUC of the ABSO metabolite following NTB was significantly ( P = 0.014) lower in 1-month- than in 8-month-old sheep.

Determination of albendazole metabolites in plasma by HPLC.

Albendazole is an antihelminthic agent belonging to the benzimidazole class and has been used successfully in the treatment of neurocysticercosis. We report here a method for the determination of the two major albendazole metabolites in plasma, albendazole sulfone and albendazole sulfoxide. The method consists of drug extraction from 500 microL of plasma previously acidified with chloroform-isopropanol (9:1, v/v) and extract purification with n-hexane immediately before chromatographic analysis. Separation of drugs and of the internal standard (mebendazole) was performed on an RP-18 column using acetonitrile-0.25N sodium acetate buffer (3:7, v/v), pH 5.0, as the mobile phase and using detection at 290 nm.

Aquatic photodegradation of albendazole and its major metabolites. 1. Photolysis rate and half-life for reactions in a tube

Aquatic photodegradation of albendazole (ABZ) and its three major metabolites, albendazole sulfoxide (ABZSO), albendazole sulfone (ABZSO 2 ), and 2-aminoalbendazole sulfone (ABZ2NH 2 ), was studied under natural sunlight. The sunlight exposures were conducted in solution at pH 5, 7, and 9 to encompass conditions of reversible ionization or protonation of the test substances. The photodegradation rate constants and half-lives were determined for the test substances. An HPLC method was used to measure the disappearance of chemical in solution with time

Interaction of benzimidazole anthelmintics with Haemonchus contortus tubulin: Binding affinity and anthelmintic efficacy

The ability of various benzimidazoles (BZs) to bind tubulin under different conditions was assessed by determining their IC 50 values (the concentration of unlabeled drug required to inhibit 50% of the labeled drug binding), K a (the apparent equilibrium association constant) and B max (the maximum binding at infinite [BZ]= [drugreceptor]). The ability of unlabeled benzimidazoles—fenbendazole, mebendazole (MBZ), oxibendazole (OBZ), albendazole (ABZ), rycobendazole (albendazole sulfoxide, ABZSO), albendazole sulfone, oxfendazole (OFZ), and thiabendazole—to bind tubulin was determined from their ability to inhibit the binding of [ 3H]MBZ or [ 3H]OBZ to tubulin in supernatants derived from unembryonated eggs or adult worms of Haemonchus contortus. The binding constants (IC 50, K a , and B max) correlated with the known anthelmintic potency (recommended therapeutic doses) of the BZ compounds except for OFZ and ABZSO whose K a values were lower than could be expected from anthelmintic potency. The binding of [ 3H]ABZ or [ 3H]OFZ to tubulin in supernatants derived from BZ-susceptible and BZresistant H. contortus was compared. [ 3H]ABZ demonstrated saturable high-affinity binding but [ 3H]OFZ bound with low affinity. The high-affinity binding of [ 3H]ABZ was reduced for the R strain. Tubulin bound BZ drugs at 4 °C with lower apparent K a than at 37 °C.

Simultaneous Pharmacokinetic Modeling of a Drug and Two Metabolites: Application to Albendazole in Sheep

U Albendazole pharmacokinetic parameters were determined in lambs after iv, oral, and intraruminal single administrations. The parent drug and two metabolites, albendazole sulfoxide and albendazole sulfone, we'e simultaneously determined in whole blood, plasma, and urine using an HPLC method. The parent drug was only recovered in plasma when injected intravenously. For other routes, only the two metabolites were detectable; they were present in red blood cells and plasma at equal concentrations. The pharmacokinetic parameters were determined by using compartmental models which simultaneously described the two oxidative steps and the urinary excretion of the sulfoxide derivative. Dose-dependent pharmacokinetics was studied in the dose range 0.95-3.8 mg/kg. The results showed that clearance remained constant within the tested dose range since the area under the curve normalized to the dose was similar in the cases of sulfoxide and sulfone metabolites, whatever the route of administration. The drug appeared to be extensively metabolized in the body regardless of the route of administration. Sulfoxidation probably took place in liver, but other tissues seemed to be responsible for the formation of the sulfoxide which has been described as the major anthelmintic derivative of albendazole.

Simultaneous Pharmacokinetic Modeling of a Drug and Two Metabolites: Application to Albendazole in Sheep

U Albendazole pharmacokinetic parameters were determined in lambs after iv, oral, and intraruminal single administrations. The parent drug and two metabolites, albendazole sulfoxide and albendazole sulfone, we'e simultaneously determined in whole blood, plasma, and urine using an HPLC method. The parent drug was only recovered in plasma when injected intravenously. For other routes, only the two metabolites were detectable; they were present in red blood cells and plasma at equal concentrations. The pharmacokinetic parameters were determined by using compartmental models which simultaneously described the two oxidative steps and the urinary excretion of the sulfoxide derivative. Dose-dependent pharmacokinetics was studied in the dose range 0.95-3.8 mg/kg. The results showed that clearance remained constant within the tested dose range since the area under the curve normalized to the dose was similar in the cases of sulfoxide and sulfone metabolites, whatever the route of administration. The drug appeared to be extensively metabolized in the body regardless of the route of administration. Sulfoxidation probably took place in liver, but other tissues seemed to be responsible for the formation of the sulfoxide which has been described as the major anthelmintic derivative of albendazole.

Comparison of pharmacokinetic variables for two injectable formulations of netobimin administered to calves

SUMMARY In a 4 × 4 crossover-design study, pharmacokinetic variables of 2 injectable formulations of netobimin (trisamine salt solution and zwitterion suspension) were compared after sc administration in calves at dosage of 12.5 mg/kg of body weight. Netobimin parent drug was rapidly absorbed, being detected between 0.25 and 12 hours after treatment, with maximal plasma drug concentration (Cmax) values of 2.20 ± 1.03 μg/ml achieved at 0.75 ± 0.19 hour (trisamine) and 1.37 ± 0.59 μg/ml at 0.81 ± 0.18 hour (zwitterion). Netobimin area under the plasma concentration-time curve (AUC) was 7.59 ± 3.11 μg·h/ml (trisamine) and 6.98 ± 1.60 μg·h/ml (zwitterion). Elimination half-life (t½β) was 2.59 ± 0.63 hours (trisamine) and 3.57 ± 1.45 hours (zwitterion). Albendazole was not detected at any time. Albendazole sulfoxide was detected from 4 hours up to 20 hours (trisamine) and from 6 hours up to 24 hours (zwitterion) after administration of the drug. The Cmax values were 0.48 ± 0.16 μg/ml and 0.46 ± 0.26 μg/ml for trisamine and zwitterion formulations, respectively, achieved at time to peak drug concentration (Tmax) values of 9.50 ± 1.41 hours (trisamine) and 11.30 ± 1.04 hours (zwitterion). Albendazole sulfoxide AUC was 3.86 ± 1.04 μg·h/ml (trisamine) and 4.40 ± 3.24 μg·h/ml (zwitterion); t½β was 3.05 ± 0.75 hours (trisamine) and 3.90 ± 1.44 hours (zwitterion). Albendazole sulfone was detected from 4 (trisamine) or 6 hours (zwitterion) to 24 hours after treatment. The AUC was 6.98 ± 1.60 μg·h/ml (trisamine) and 10.51 ± 7.41 μg·h/ml (zwitterion); Cmax was 0.76 ± 0.21 μg/ml at Tmax of 12.00 ± 1.85 hours (trisamine) and 0.70 ± 0.24 μg/ml at Tmax of 12.50 ± 2.33 hours (zwitterion). Albendazole sulfone t½β was significantly (P &lt; 0.05) longer for the zwitterion formulation (7.77 ± 4.72 hours) than for the trisamine salt (2.87 ± 0.61 hours). Albendazole sulfone AUC was higher than albendazole sulfoxide AUC, resulting in AUC ratio of 1.8 (trisamine) and 2.4 (zwitterion). The 2 formulations were not significantly different in terms of AUC or Tmax for netobimin and albendazole sulfone, AUC for albendazole sulfoxide, or t½β for netobimin and albendazole sulfoxide. It was concluded that the 2 netobimin injectable formulations were bioequivalent. Experimental phase had a significant effect on the AUC and Cmax for albendazole sulfoxide and on the Cmax for netobimin. One possible explanation for the differences between phases could be induction of liver microsomal enzymes by netobimin and its metabolites, resulting in increased rate of metabolism during phase 2 of the study.

Therapeutic Monitoring of Albendazole

A sensitive and specific reversed-phase high-performance liquid chromatography (HPLC) method is described for the quantitative determination of albendazole sulfoxide (ASOX); since albendazole sulfone (ASON) appears only in small amounts and albendazole (ABZ) normally does not appear in human plasma, only a qualitative determination of ASON and ABZ was made in human plasma. Plasma samples were extracted three times using ethylacetate and petroleum benzine; this yielded optically clear samples which after evaporation were dissolved in the HPLC solvent and injected onto an RP-C18 column, with ultraviolet detection at 290 nm. The detection limit of the main metabolite ASOX was 50 nM and that of ASON was 100 nM. The intraday coefficient of variation for ASOX was 3.3% at a concentration of 2.2 microM, and the interday coefficients of variation were 14.5, 7.3, and 9.1% at ASOX concentrations of 0.5, 2.5, and 5.0 microM, respectively. Calibration was linear in a concentration range of 0.05-12 microM for ASOX and 0.1-8 microM for ASON, respectively. Pharmacokinetic data of a patient with echinococcosis are presented.

Direct separation of albendazole sulfoxide enantiomers by liquid chromatography on a chiral column deriving from (S)-N-(3,5-dinitrobenzoyl) tyrosine: application to enantiomeric assays on plasma samples.

The direct enantiomeric resolution of albendazole sulfoxide (SOABZ), an anthelmintic drug belonging to the benzimidazole class, is reported on a chiral stationary phase (CSP) synthesized by covalent binding of (S)-N-(3,5-dinitrobenzoyl)tyrosine-O-(2-propen-1-yl) methyl ester on a gamma-mercaptopropyl-silanized silica gel. A comparison with the resolution achieved on commercially available Pirkle-type CSPs obtained from N-(3,5-dinitrobenzoyl) derivatives of (R)-phenyglycine or (S)-phenylalanine is described. Some structurally related chiral sulfoxides including oxfendazole (SOFBZ) are also studied. Optimization of the mobile phase nature and composition is investigated showing that a hexane-dioxane-ethanol ternary mixture affords an almost baseline resolution (Rs = 1.25); however, in this case, albendazole sulfone (SO2ABZ) is eluted between the two sulfoxide enantiomers; accordingly, a hexane-ethanol mobile phase would be preferred for biological samples containing both metabolites. The influence of temperature on the resolution is depicted with a hexane-ethanol mobile phase. Finally, application to the enantiomeric assays of SOABZ in plasmatic extracts of rat, sheep, bovin, and man after oral administration of albendazole (sulfoxidized to SOABZ and SO2ABZ) is reported. Some distortions in the enantiomeric ratios are evidenced depending on the species.